Tyrosine derivatives

ABSTRACT

The L-antipode of 4-methoxy-m-tyrosine and lower alkyl esters thereof which are useful as anti-parkinson agents.

United States Patent [191 Kaiser et' a1.

[ 1 Dec. 10, 1974 TYROSINE DERIVATIVES [75] Inventors: Ado Kaiser,Neu-Frenkendorf;

Wolfgang Koch, Riehen; Marcel Scheer, Basel; Uwe Wolcke, Bottmingen, allof Switzerland [73] Assignee: Hoffmann-La Roche Inc., Nutley,

[22] Filed: Nov. 3, 1971 [21] App]. No.: 195,472

30 Foreign Application Priority Data Nov. 10, 1970 Switzerland 16630/70[56] References Cited UNITED STATES PATENTS 3,344,023 9/1967 Reinhold eta1. 26/471 A Daeniker 260/471 A Hegedus et al. 260/471 A OTHERPUBLICATIONS Wagne, R. B. et 211.; Synthetic Organic Chemistry; (1967),pub. by John Wiley & Sons (N.Y.), QD262W24, page 494.

Royals, E. B; Advanced Organic Chemistry; (1961), pub. by Prentice-Hall,Inc., page 578,

Finar, I. L.; Organic Chemistry; (1963), pub. by Richard Clay and Co.,Inc., (England); page 199.

Primary ExaminerLorraine A. Weinberger Assistant ExaminerL. A. ThaxtonAttorney, Agent, or Firm-Samuel L. Welt; Jon S. Saxe; George M. Gould [57 ABSTRACT The L-antipode of 4-methoxy-m-tyrosine and lower alkyl estersthereof which are useful as anti-parkinson agents.

17 Claims, No Drawings TYROSINE DERIVATIVES SUMMARY OF THE INVENTION Inaccordance with this invention, it has been found that the L-antipode ofa compound of the formula:

wherein R is hydrogen or lower alkyl; and pharmaceutically acceptablesalts thereof are useful in reducing the symptons of parkinson diseasesuch as rigor, 'akinesi'a and tremor, without causing peripheraladrenergic effects and other undesirable secondary effects.

In accordance with this invention, the L-antipode of formula I can beprepared by resolving a racemic mixture of the compound of formula Iabove into its optical antipodes and isolating the L-antipode of acompound of formula I above or a pharmaceutically acceptable saltthereof.

On the other hand, the compound of formula I can be prepared from acompoundof formula:

I R1 Bl. 11

wherein R is an amino group protected by aconventional amino protectinggroup convertible to an amino group; R is hydroxy or hydroxy protectedby a conventional hydroxy protecting group convertible to a hydroxygroup; R is carboxy or a conventional carboxy protecting groupconvertible to a carboxy group; or a pharmaceutically acceptable saltthereof, by simultaneously, or any sequence, converting the protectedamino group into free amino groups, converting the protected hydroxygroup into free hydroxy groups, and/or converting the protected carboxygroup into the free acid. The free acid can, if desired be'convertedinto its salt form.

DETAILED DESCRIPTION As used throughout this application, the term loweralkyl designates both straight chain and branched chain alkyl groupscontaining from 1 to 7 carbon atoms such as methyl, ethyl, isopropyl,n-hexyl, etc. Among the preferred alkyl groups are included methyl andethyl.

The compounds of formula I above are amphoteric in character. Thesecompounds dissolve in water as well as in acids or in alkalies in whichthey form salts.

acid, succinic acid, maleic acid, methanesulfonic acid,p-toluenesulfonic acid and the like. Such acid addition salts are alsowithin the scope of the invention. Among the bases with which-thecompounds of formula I form salts are the alkali metal bases such assodium hydroxide, potassium hydroxide, etc., and ammonia.

The resolution of the racemate of formula I to produce the L-antipode offormula I can be carried out by conventional methods of resolvingracemic mixture. For example, a racemic ester of formula I can beresolved using optically active acids such as camphorsulfonic acid,tartaric acid or tartaric acid-2,4-dichloro anilide. The resolution of aracemic free acid of formula I can be carried out using optically activebases such as ephedrine, dehydroabietylamine or the like, as well asoptically active acids such as camphorsulfonic acid.

The isolution of the desired L-antipodes can be carried out byconventional isolation methods such as crystallization of the salts anddecomposition thereof.

In accordance with this invention, R in the compound of formula II can.be any conventionally protected amino group. Among the conventionalamino protecting groups are those which can beremoved by hydrogenolysisor hydrolysis. Examples of protected amino groups which are convertibleinto the free amino group (R, in the starting materials of formula II)are the following:

A. Groups which are convertible into the free amino group by hydrolysissuch as, for example, lower alkanoylamino groups, the formylamino group,the benzoylamino group and the tertbutoxycarbonylamino group. Theformylamino group, the lower alkaoylamino groups, especially theacetoamino group, and the benzoylamino group are preferred.

The hydrolysis of these groups can be carried out in a manner known perse with acids, especially with strong mineral acids such as with aqueoushydrochloric acid or sulfuric acid. The hydrolysis can be carried out atroom temperature, but it is preferably carried out at an elevatedtemperature up to the boiling point of the mixture.

B. Groups which are convertible into the free amino group byhydrogenolysis such as, for example, the benzyloxycarbonylamino group orthe dibenzylamino group. 7

Any conventional method of hydrogenolysis can be utilized to removethese groups. For example, hydrogenolysis can be carried out byhydrogenation in the presence of a hydrogenation catalyst. As catalyststhere can be used, for example, palladium/charcoal catalysts or platinumcatalysts, in which case the hydrogenolysis is expediently carried outin a lower alkanecarboxylic acid such as glacial acetic acid or in alower alkanol such as methanol or ethanol. Aqueous alkanols may also beused.

C. Groups such as, for example, the 0- or pnitrophenylthioamino groupwhich can be converted into the free amino group by treatment with acid,for example with aqueous hydrochloric acid, preferably in the presenceof thiophenol.

In accordance with this invention, R in the compound of formula II canbe any conventional hydroxy protecting group. Among these protectinggroups are the protecting groups which can be removed by hydrogenolysisor hydrolysis. Examples of groups which are convertible into the hydroxygroup (R in the starting materials of formula ll) are the following:

D. Groups which are convertible into the hydroxy group by hydrolysissuch as, for example, lower alkanoyloxy groups, especially the acetoxygroup, the formyloxy group and the benzoyloxy group.

The hydrolysis of these groups can be carried out by 7 conventionalhydrolysis techniques such as with alkalies (e.g., with aqueous oraqueous-alcoholic sodium hydroxide or potassium hydroxide) or with acids(e.g., aqueous hydrochloric acid or sulfuric acid). The hydrolysis canbe carried out at a temperature from about C. up to the boiling point ofthe mixture.

Further, R can represent an etherified hydroxy group such as amethoxy-methoxy group or a tetrahydropyranyloxy group which can beconverted into the hydroxy group by hydrolysis with acids (e.g., withaqueous hydrochloric acid).

E. Groups which are convertible into the hydroxy group by hydrogenolysissuch as, for example, the benzyloxy group.

The hydrogenolysis of this group can be carried out In accordance withthis invention, R in the compound of formula ll can be any conventionalcarboxylic acid protecting group. Among the preferred protecting groupsare the groups which can be removed by either hydrolysis orhydrogenolysis. Examples of groups which are convertible into thecarboxyl group (R in the starting materials of formula II) are thefollowing:

G. Groups which are convertible into the carboxyl group by hydrolysissuch as, for example, lower alkoxycarbonyl groups (especially themethoxycarbonyl and ethoxycarbonyl groups) and amide groups; that is tosay, amide groups derived from the free amino group and from primary orsecondary amides such as the carbamoyl group and monoor di-alkylorarylsubstituted carbamoyl groups, in which case the alkyl groups cancontain from 1 to 7 carbon atoms and the aryl group is especially thephenyl group. i

A further group which is convertible into the carboxyl group in a mannerknown per se is the cyano group.

The hydrolysis of the foregoing groups can be carried out according toconventional hydrolysis techniques using acids or bases. I

H. Groups which are convertible into the carboxy group by hydrogenolysissuch as, for example, the henzyloxycarbonyl group.

The hydrogenolysis of such a group can be carried out in an 1 analogousmanner to the hydrogenolysis methods described hereinbefore.

The conversion of aprotected amino group R, to the free amino group andthe conversion of a group which may be present which is convertible intothe hydroxy group or into the carboxyl group (R, and R into the hydroxygroup or into the carboxyl group can be carried out in any desiredsequence or simultaneously.

If desired, a free acid obtained can be converted into a lower alkylester (R represents a lower alkyl group). This can be carried out byconventional esterification techniques such as using the usualesterification agents (e.g., an appropriate lower alkanol).

Furthermore, bases obtained can be converted into salts if desired; theL-antipodes of the. free amino acid of formula I forming both acidaddition salts and metal salts. Examples of acid addition salts arethose with inorganic acids such as hydrochloric acid and those withorganic acids such as oxalic acid. Examples of metal salts are, inparticular, the alkali metal salts.

. The preferred starting materials of formula ll are those in which Rrepresents a lower alkanoalamino group, especially the acetam'ino group,the formylamino group or the benzoylamino group.

Another group of preferred starting materials of formula I! comprisesthose in which R represents the hydroxy group, the formyloxy group or alower alkanoyloxy group, especially the acetoxy group.

A further preferred group of starting materials of formula [I comprisesthose in which R represents the carboxyl group or a lower alkoxycarbonylgroup, especially the methoxycarbonyl group or the ethoxycarbonyl group.

The starting materials of formula ll are, in part, known and, in part,new.

The new starting materials, namely the L-antipodes of compounds of thegeneral formula:

wherein R and R are as above; and R is formyloxy or lower alkanoyloxy;and their salts, can be prepared by oxidizing the L- antipode of acompound of the general formula:

wherein R and R are as above;

and R is formyl or lower alkanoyl; with a peracid. 1

As peracids there can be used organic peracids, especiallyperalkanecarboxylic acids such as peracetic acid, performic acid,trifluoroperacetic acid and the like, the oxidation being preferablycarried out in a lower alkanecarboxylic acid such as formic acidandacetic acid. Aromatic percarboxylic acids such as mchloroperbenzoicacid can also be used as the peracid, in which case the oxidation isexpediently carried out in an organic solvent such as methylene chlorideor chloroform. The oxidation with a peracid is expediently carried outat a temperature of about 0C. to about 50C.

The L-antipode of a compound of formula ll-B obtained by the foregoingoxidation can subsequently be converted into corresponding compoundswherein R represents the hydroxy group by mild alkaline hydrolysis. Thishydrolysis can be carried out, for example,

with aqueous sodium hydroxide or potassium hydroxide at roomtemperature. If an excess of caustic alkali is used, an alkoxycarbonylgroup R, can be simultaneously hydrolyzed to the carboxyl group.

The hydrolysis of a compound of formula II-B with conversion of aformyloxy group R into a hydroxy group can also be carried out by mildacidic hydrolysis, for example, with aqueous hydrochloric acid at roomtemperature or by Kieselgel chromatography.

The known starting materials of formula II can be prepared in ananalogous manner (peracid oxidation and subsequent mild hydrolysis).

The compounds of formula III can in turn be obtained from a compound ofthe formula:

wherein R and R are as above.

Compounds of formula III where R is formyl can be obtained, for example,by reacting the compound of formula IV above with a formylation agent inthe presence of a Lewis acid. Any conventional method of formylating canbe utilized to prepare the compound of formula III where R is formyl.Among the-formylation agents there can be used, for example, a formicacid ester, an orthoformic acid ester, formylchloride, a dihalomethyllower alkyl ether, especially a dichloromethyl lower alkyl ether such asdichloromethyl methyl ether, hydrocyanic acid, dimethylformamide orother amides of formic acid. This reaction can take place in thepresence of any conventional Lewis acid. As the Lewis acid there canexpediently be used a zinc halide such as zinc chloride, an aluminumhalide such as aluminum chloride, a titanium halide such as titaniumtetrachloride, an iron trihalide such as iron trichloride o a tin halidesuch as tin tetrachloride.

The formylation reaction can be carried out in the absence of a furthersolvent if the formylation agent is used in excess. On the other hand,the formylation reaction can also be carried out in the presence of aninert organic solvent (e.g., nitrobenzene, carbon tetrachloride,methylene chloride or chloroform). The reaction temperature can varywithin a very wide range. Generally, it is preferred to use atemperature of from about 50C. and the reflux temperature of thereaction mixture.

Compounds of formula Ill in which R represents a lower alkanoyl group(e.g., the acetyl group) can be obtained, for example, by reacting thecompound of formula IV with a functional derivative of a loweralkanecarboxylic acid (e.g., acetic acid) in the presence of aFriedel-Crafts catalyst. Asthe Friedel-Crafts catalyst there can be usedespecially a strong Lewis acid;

for example, boron trifluoride, an aluminum trihalide (e.g., aluminumtrichloride), a titanium tetrahalide (e.g., titanium tetrachloride) oraniron trihalide (e.g., iron trichloride). Any conventional reactivefunctional derivative of a lower alkane carboxylic acid can be used inthis reaction. As the functional derivatives of the lower alkanecarboxylic acids there are especially used acid halides (e.g., acetylchloride). The reaction is expediently carried out in an organic solvent(e.g., nitrobenzene) at a temperature between about 0and 200C.

The present invention is also concerned with pharmaceutical preparationshaving anti-parkinsoon activity.

The pharmaceutical preparations provided by the present inventioncontain as an essential active ingredient the L-antipode of a compoundof formula I or a pharmaceutically acceptable salt thereof incombination with a compatible pharmaceutical carrier.

On administration of such a preparation, the typical symptons ofiodiopathic parkinsonism such as rigor, akinesia and tremor can besignificantly improved or abolished without peripheral adrenergiceffects and other undesirable secondary effects thereby occurring.

The compounds of formula I and their salts can be used as medicaments;for example, in the form of pharmaceutical preparations which containthem in association with a compatible pharmaceutical carrier which canbe an organic or inorganic inert carrier material suitable for enteralor parenteral administration such as, for example, water, gelatin, gumarabic, lactose, starches, magnesium stearate, talc, vegetable oils,polyalkylene glycols, petroleum jelly, etc. The pharmaceuticalpreparations can be made up in solid form (e.g., as tablets, dragees,suppositories or capsules) or in liquid form (e.g., as solutions,suspensions or emulsions). The preparations may be sterilized and/or maycontain adjuvants such as preserving, stabilizing, wetting oremulsifying agents, salts for varying the osmotic pressure or buffers.They can also contain other therepeutically valuable substances.

In comparison the L-dopa, a,known antiarkinson agent, the activeingredients aforesaid (i.e., the compounds of formula I or saltsthereof) and the pharmaceutical preparations provided by the presentinvention possess a depot action (half-life 45 hours). The LD in themouse amounts to more than 5,000 mg./kg. p.o. in the 24-hour test. Onadministration of the pharmaceutical preparations provided by thepresent invention, the undesirable secondary effects which usuallyappear on administration ofL-dopa, namely gastrointestinal complaints,involuntary movements and circulatory complaints, do not occur or onlyoccur to a very slight extent.

The pharmaceutical preparation provided by the present invention can bemade up in solid or liquid form and, in addition to the essential activeingredient, can contain suitable pharmaceutical organic or inorganiccarrier materials such as water, gelatin, lactose, magnesium stearate,talc or the like. The pharmaceutical preparations can be made up insolid forms such as tablets, dragees or capsules or in liquid forms suchas solutions, suspensions or emulsions. Tablets are preferred. u

A pharmaceutical preparation in dosage unit form can expediently containabout 50 mg. to about 1,000 mg., preferably about 500 mg. to about 1,000mg. of active ingredient.

The pharmaceutical preparations can also contain one or more peripheraldecarboxylase inhibitors,

whereby a reduction of the amount of active ingredient to beadministered is made possible. As the decarboxylase inhibitor there canbe used any pharmaceutically For this purpose there can be used as thedecarboxylase inhibitor a compound of the general formula:

R-NH-NH-CHiQ wherein R is a hydrogen, amino-(lower alkanoyl),amino-(hydroxy lower alkanoyl; and n is-an integer from 2 to 3; or apharmaceutically acceptable salt thereof.

For example, there can beused as the decarboxylase inhibitor:

N-D,L-seryl-N -(2,3,4-trihydroxybenzyl)-hydrazide;

dihydroxyphenyl)-2-methyl-alanine and compounds of the general formula:

wherein Q is hydrogen or lower alkyl; aswell as3,4-dihydroxy-benzyloxyamine and salts thereof.

Where the present pharmaceutical preparations contain a decarboxylaseinhibitor, the weight ratio of active ingredient to decarboxylaseinhibitor expediently amounts to about 5:1 to 10:1.

The pharmaceutical preparations provided by the present invention can bemanufactured by mixing the L-antipode of a compound of formula 'I or apharmaceutically acceptable salt thereof, if desired together with aperipheral decarboxylase inhibitor, with a compatible pharmaceuticalcarrier material suitable for medicinal administration. As the carriermaterial there can be used the carrier materials which are usual in Ipharmacy.

rier materials or such a preparation can be manufactured byincorporating the active ingredient into a core, providing this with acoating which is resistant to gastric juice and applying thereover anexternal layer which contains the decarboxylase inhibitor. In thismanner there is provided a pharmaceutical preparation from which theactive ingredient is released with delay only after the decarboxylaseinhibitor has been released, preferably about 30 to 60 minutes after thedecarboxylase inhibitor. This has been found to be especially expedient.In the case of parenteral administra- .8 tion, the decarboxylaseinhibitor is expediently administered first, expediently intravenously,andthe active ingredient is administered about 30 to 60 minutes later.

In the treatment of Parkinsonism, the active ingredient, optionallyincombination with a peripheral decarboxylase inhibitor, can beadministered either orally or parenterally, especially intravenously.

The amount of active ingredient to be administered per day is governedby the particular case.

In general, in the case of oral administration, an amount of activeingredient of about 1.5 to about 4 g. especially about 3 g., will beemployed. In the case of intravenous administration, the amount ofactive ingredient to be administered per day can lie between about 50mg. and about 2 g., especially at about 1 g.

The foregoing amounts relate to the active ingredient content calculatedas 4-methoxy-L-m-tyrosine which represents a preferred active ingredientin accordance with the present invention.

As has already been mentioned, the amount of active ingredientadministered can be reduced by the combined administration thereof witha peripheral decarboxylaseinhibitor. In the case of such a combinedadministration, there are expediently used amount of active ingredientwhich lies in the lower part of the foregoing ranges. For example, 1 g.of active ingredient and mg. of a decarboxylase inhibitor (ratio 10:1parts by weight) or 500 mg. of active ingredient and 100 mg. ofdecarboxylase inhibitor (ratio 5:1 parts by weight) can be administeredorally per day.

The administration is expediently effected in individual doses dividedover the day.

The following examples are illustrative but not limitative of theinvention. All temperatures are in degrees centigrade. 40 percentperacetic acid refers to percent by weight. The term concentratedhydrochloric acid refers to a hydrogen chloride content of 38 percent byweight.

EXAMPLE 1 A mixture of 5.3 g. (19.9 mmol) of N-acetyl-4-methoxy-L-m-tyrosine methyl ester-and of 100 ml. of 3-N aqueoushydrochloric acid is heated at reflux in an argon atmosphere for 2hours. The 4-methoxy-L-m- EXAMPLE 2 3.3 g. (13.3 mmol) of4-methoxy-L-m-tyrosine hydrochloride are dissolved in ml. of ethanol and12.5 ml. of propylene oxide are added to the solution in severalportions in'the course of 3 hours. The mixture is then left to stand at25C. for 20 hours and the precipitated crystals are filtered off. Thepure 4-methoxy-L-m-tyrosine is obtained by one recrystallization from 40ml. of absolute ethanol to which a few drops of water are added. Yield:2.15 g.; melting point 25 l-252C.; [01],, =34.2 (c l percent in water).

150 ml. of glacial acetic acid is left to stand at 25C. for 23 hours andthen evaporated under reduced pressure. 200 ml. of saturated aqueoussodium hydrogen carbonate solution are added to the residue and it isextracted twice with 250 ml. of ethyl acetate each time. The extractsare combined, dried over sodium sulphate and evaporated. The residueconsists of a mixture of N- acetyl-4-methoxy-L-m-tyrosine methyl esterand its formate, i.e., N-acetyl-3-(3-formyloxy-4-methoxyphenyl)-L-alanine methyl ester. The hydrolysis of the formateto N-acetyl-4-methoxy-L-mtyrosine methyl ester is completed bychromatography of this mixture on a column containing 3,000 g. ofsilicagel [elution with ethyl acetate/toluene (l:l parts by volume)] and16.8 g. (63 percent) of the desired compound are obtained after onerecrystallization from ethyl acetate/ether. Melting point 9798C.; [01],,25 +3l.5 (c 2 percent in 95 percent ethanol).

EXAMPLE 4 167 ml. of titanium tetrachloride are added with stirring inthe course of 5 minutes to a solution of 95 g. ofN-acetyl-3-(p-methoxyphenyl)-L-alanine methyl ester in 1500 ml. ofnitrobenzene, the temperature rising to 38C. The mixture is cooled to+23C., 69.4 ml. of dichloromethyl methyl ether are then added in thecourse of 3 minutes and the mixture is stirredat room temperature for 2hours. The solution is cooled to +5C. and poured with stirring into 380ml. of ice-cold 3-N aqueous hydrochloric acid. 4,000 ml. of ethylacetate and 2,000 ml. of tetrahydroduran are added, the mixture isneutralized by the introduction with stirring of 1,200 g. of anhydrouspotassium carbonate and dried over sodium sulphate. After filtration,the filtrate is evaporated (finally in a high vacuum at 70C.). Theresidue is dissolved in 500 ml. of methylene chloride and applied to achromatographic column containing 200 g. of silicagel. Elution withethyl acetate/methylene chloride (1:1; v/v) yields, after evaporation,72 g. of N- acetyl-3-( 3 -formyl-4-methoxyphenyl )-L-alanine methylester which can be further purified by recrystallization from ethylacetate/hexane.

EXAMPLE 5 The N-acetyl-3-( p-methoxyphenyl )-L-alanine methyl ester canbe obtained by esterification with methanol of the corresponding freeacid by the procedure given in Example 9 hereinafter.

EXAMPLE 6 By the procedure described in Examples 1 and 2, 4-methoxy-L-m-tyrosine and its hydrochloride are obtained fromN-acetyl-4-methoxy-L-m-tyrosine ethyl ester [melting point ll9120C.;[01],, 25 +25.4 (c 2 percent in 95 percent ethanol)].

EXAMPLE 7 The Nacetyl-4-methoxy-L-m-tyrosine ethyl ester can be obtainedby the procedure described in Example 3 (oxidation with peracetic acidin glacial acetic acid and hydrolysis) from N-acetyl-3-(3-formyl-4-methoxyphenyl)-L-alanine ethyl ester [melting point l-l0lC.; [041 25+240 (0 1.0 percent in 95 percent ethanol)].

EXAMPLE 8 The N-acetyl-3-(3-formyl-4-methoxyphenyl)-L- alanine ethylester is obtained by the procedure de- 10 scribed in Example 4 byforrnylation of N-acetyl-3-(pmethoxyphenyl)-L-alanine ethyl ester[melting point 9394.5C.; [04],, 25 +23.3 (c 1.0 percent in 95 percentethanol)].

EXAMPLE 9 Dry hydrogen chloride gas is led into a solution of 160 g. ofN-acetyl-3-(p-methoxyphenyl)-L-alanine in 1,600 ml. of absolute ethanoluntil the solution is saturated, the temperature of the solution beingheld at 20-22C. by cooling (duration 2.5 hours). The solution is thenevaporated under reduced pressure, the residue taken up in ethylacetate, the solution obtained washed with saturated aqueous sodiumhydrogen carbonate solution, dried over sodium sulphate and then againevaporated under reduced pressure. The crystalline residue isrecrystallized from a mixture of ethyl acetate and hexane. PureN-acetyl-3-(p-methoxyphenyl)- L-alanine ethyl ester is thus obtained.

EXAMPLE 10 By the procedure described in Examples 1 and 2, 4-methoxy-L-m-tyrosine and its hydrochloride are obtained fromN-acetyl-4-methoxy-L-m-tyrosine [melting point l34l35C; [01], 25 =+55.7(c= 2 percent in 95 percent ethanol)].

EXAMPLE 11 EXAMPLE 12 47.4 g. of N-acetyl-3-(p-methoxyphenyl)-L-alanineare added to a solution of g. of anhydrous aluminium chloride in 200 ml.of nitrobenzene. The solution thus obtained is cooled to +14C. and then,without further cooling, 45 ml. of acetyl chloride are added in oneportion with stirring. The temperature rises immediately to 29C. After20 minutes, the solution is poured onto a mixture of 10 ml. ofconcentrated aqueous hydrochloric acid and 400 g. of ice. The mixture isextracted twice with 400 ml. of ethyl acetate each time. The extractsare washed twice with 100 ml. of saturated aqueous sodium chloridesolution each time, then dried over sodium sulphate and concentrated toa volume of about 600 ml. under reduced pressure. Crystallization occurson cooling this solution to 0C. The solution is filtered, the crystalswashed with ethyl acetate and dried under reduced pressure. PureN-acetyl-3-(3- acetyl-4-methoxyphenyl)-L-alanine is thus obtained.Yield: 41 g. Melting point l59l60 C.; [01],, 25 +52.5 (c 2 percent inpercent ethanol).

EXAMPLE 13 A solution of 29.2 g. of N-acetyl-3-(3-acetyl-4-methoxyphenyl)-L-alanine in 40 g. of 40 percent peracetic acid inglacial acetic acid is held at a temperature of 30C. for 2.5 hours bycooling at the beginning and warming somewhat towards the end.N,O-diacetyl- 4-me'thoxy-L-m-tyrosine is obtained by evaporation of thesolution in a vacuum. Yield 30.9 g.

EXAMPLE 14 4.38 ml. of titanium tetrachloride are rapidly added dropwiseto a suspension of 2.37 g. of N-acetyl-3-(pmethoxyphenyl)-L-alanine in40 ml. of nitrobenzene,

the temperature rising to 40C. and there resulting a dark-brownsolution. The solution is cooled to 30C., 1.82 ml. of dichloromethylmethyl ether are added dropwise in the course of IO minutes and themixture is stirred for 20 minutes. The mixture is then poured onto 20ml.- of ice-cold aqueous solution percent by I weight of hydrochloricacid and extracted three times zation of the residue from ethyl acetate.Yield: 0.8 g.-

Melting point 129-l30C.; [0:1 25: +560 (c 2.0 percent in 95 percentethanol).

EXAMPLE A solution of 26.5 g. (0.1 mol) of N -acetyl.-3-( 3-formyl-4-m'ethoxyphenyl),-L alanine, g. of. 40 percent peraceticacid inglacial aceticacid and 150 ml. of glacial acetic acid is left to standat room temperature for 23 hours and then evaporated under reducedpressure. The residue consists of a mixture of N-acetyl-4-'methoxy-L-m-tyrosine and its formate, i.e., acetyl-3-(3-formyloxy-4smethoxyphenyl)-L-alanine. This mixture is dissolved in100 ml. of 3-N aqueous sodium hydroxide in order to complete thehydrolysis of the formate to N-acetyl-4-methoxy-L-m-tyrosine. Thesolution is left to stand at C. for 10 minutes, then acidit'red to pH2.0 with 6-N aqueous sulphuric acid and extracted with ethyl acetate.The extract is dried over sodium sulphate and evaporated. Onerecrystallization of the residue from ethyl acetate yields N-acetyl-4-methoxy-L-m-tyrosine. Yield: 18 g. Melting point l34-l35C.; [01],,=+55.7 (c= 2 percent in 95 percent ethanol).

EXAMPLE 16 A solution of 8.3 g. mmol) of N-acetyl-4-methoxy-L-m-tyrosine ethyl ester in 50 ml. of 3-N sodium hydroxide isleft to stand at 25C. for 0.5 hour, then acidified to pH 2.0 with 6-Naqueous sulphuric acid and extracted with ethyl acetate. The extract isdried over sodium sulphate and evaporated. One recrystallization fromethyl acetate yields pure N-acetyl- 4-methoxy-L-m-tyrosine.

EXAMPLE l7 4-Methoxy-L-m-tyrosine is obtained by the procedure describedin Example 1 and Example 2, there being used, instead of N-acetyl-4-methoxy-L mtyrosine methyl ester or N-acetyl-4- methoxy-L-m-tyrosineethyl ester, N,O-diacetyl-4- methoxy-L-m-tyrosine ethyl ester.

EXAMPLE 18 A solution of 32.2 g. of N-acetyl-3-(3-acetyl-4-methoxyphenyl)-L-alanine ethyl ester in 40 g. of 40 percent peraceticacid in glacial acetic acid is held at a temperature of 30 for 2.5 hoursby cooling at the beginning and warming somewhat towards the end. N,O-diacetyl-4-methoxy-L-m-tyrosine ethyl ester is obpressure.

EXAMPLE 19 5.3 g. of N-acetyl-3-(p-methoxyphenyl)-L-alanine ethyl esterare added to a solution of 10.7 g. of aluminium chloride in 80 ml. ofnitrobenzene. The solution thus obtained is cooled to +19C. and then,without further cooling, 3 ml. of acetyl chloride are added in oneportion with stirring. The temperature rises immediately to 26C. After15 minutes, the solution is poured onto a mixture of 10 ml. ofconcentrated aqueous hydrochloric acid and 50 g. of ice. The mixture isextracted twice with 150 ml. of ethyl acetate each time. The extractsare washed once with 50 ml. of water and twice .with 50 ml. of saturatedaqueous sodium hydrogen carbonate solution each time, then dried oversodium sulphate and evaporated under reduced pressure. Pure N-acetyl-3-(3-acetyl-4methoxyphenyl)- L-alanine ethyl ester is obtained by onerecrystallization of the crystalline residue from a mixture of ethylaceate and diethyl ether. Yield: 4.0 g. Melting point 90-92C.; [011 2522.9 (c 2.0 percent in 95 percent ethanol).

EXAMPLE 20 the procedure described in Examples 1 and 2,

4 methoxy-L-m-tyrosine is obtained by the hydrolysis of 0acetyl-N-formyl-4-methoxy-L-m-tyrosine.

' instead of O-acetyl-N-formyl-4-methoxy-Lmtyrosine there can also beused N-formyl-4-methoxy-L- m-tyrosine which can, in turn, be obtained byhydrolysis of the O-acetyl compound in accordance with the proceduredescribed in Example 11.

The O-acetyl-N-formyl-4-methoxy-L-m-tyrosine can, in turn, be obtainedby the procedure described in Example 15 by the peracid oxidation of3-(3-acetyl-4- methoxyphenyl)-N-formyl-L-alanine which, in turn, can beobtained by the procedure described in Example 12 fromN-formyl-4-methoxy-L-phenylalanine.

EXAMPLE 21 The residue is dissolved in 500 ml. of water and, after I theaddition of 10 g. of active charcoal, heated to C. for 10 minutes. Thehot solution is filtered, washed with ml. of water and the filtrateevaporated under reduced pressure.

The residue is'dissolved in a small amount of water while gassing withargon, then adjusted to pH 4.5 to 5 by the addition of sodium carbonateand then cooled to C. for 12 hours. The precipitated crystals arerecrystallized from water. 92 g. of colorless 4-methoxy-L- m-tyrosine ofmelting point 25 l-252C. are obtained. [a] 25 34.2 (c 1 percent inwater).

EXAMPLE 22 By the procedure described in Examples 1 and 2, 4-methoxy-L-m-tyrosine is obtained from N,0-diacetyl-4-methoxy-L-m-tyrosine.

EXAMPLE 23 Dry hydrogen chloride gas is introduced over a period of 1hour into a suspension of 25 g. of 4-methoxy- L-m-tyrosine in 300 ml. ofabsolute methanol, the temperature rising to about 50C. and the4-methoxy-L-mtyrosine gradually passing into solution. The solution isthen left at room temperature for 72 hours and subsequently evaporatedat 12 mm Hg. with the addition of 100 ml. of absolute toluene.

The crystalline residue obtained is dissolved in 100- EXAMPLE 24 2.25 g.of 4-methoxy-D,L-m-tyrosine methyl ester (prepared from4-methoxy-D,L-m-tyrosine by the procedure described in Example 8 meltingpoint 6364C.) are heated on a steam-bath together with 3 g. ofL-tartaric acid 2,4dichloroanilide in ml. of isopropanol. The clearsolution obtained is cooledand an oily precipitate then separates out.The supernatant solution is decanted, digested with acetonitrile.Crystallization occurs and the crystals are recrystallized twice fromacetonitrile/methanol. The crystals obtained (the salt of4-methoxy-D,L-m-tyrosine methyl ester with L- tartaric acid2,4-dichloroanilide) are suspended in 100 ml. of ethyl acetate. Thesuspension is shaken with 50 ml. of saturated aqueous sodium carbonatesolution. The aqueous phase is separated and again washed with 50 ml. ofethyl acetate. The organic phases are combined, dried over sodiumsulphate and evaporated The following Examples illustrated typicalpharmaceutical preparations containing the phenethylamine derivativesprovided by the invention:

EXAMPLE 25 Tablets of the following composition are manufactured in theusual manner:

d-methoxy-L-m-tyrosine 500 mg. cellulose preparation AVlCEL 147.3 mg.maize starch 40 mg. methyl cellulose 10 mg. magnesium stearate 5 mg.

EXAMPLE 26 A hard gelatin capsule, from which the active ingredient isreleased with delay after the release of a decarboxylase inhibitor, canbe manufactured as follows:

A core consisting of 50 mg. of 4-methoxy-L-mtyrosine, 8 mg. of maizestarch, 15 mg. of lactose, 1.8 mg. of talc and 0.2 mg. of magnesiumstearate is coated with a cellulose acetate phthalate varnish in orderto make it resistant to gastric juice.

A granulate is manufactured from 50 mg. of N-L serine-N 2,3,4-trihydroxybenzyl )-hydrazide hydrochloride, 5.8 mg. of mannitol and2.4 mg. of polyvinylpyrrolidone in the usual manner.

The coated core and the granulate are introduced into a hard gelatincapsule.

We claim:

1. The L-antipode of the formula:

wherein R is hydrogen or lower alkyl group; or pharmaceuticallyacceptable salts thereof.

2. The antipode of claim 1 wherein R is hydrogen.

3. The antipode of claim 2 wherein said antipode is4-methoxy-L-m-tyrosine hydrochloride.

4. The antipode of claim 2 wherein said antipode is4-methoxy-L-m-tyrosine.

5. The antipode of claim 1 wherein R is lower alkyl.

6. The antipode of claim 5 wherein said antipode is4-methoxy-L-m-tyrosine methyl ester. 7. The L-antipode of the formula:

wherein R is loweralkanoylamino or formylamino; R is formyloxy or loweralkanoyloxy; R is carboxy or carbolower alkoxy.

8. The antipode of claim 7 wherein said antipode is N-acetyl 3-(3-formyloxy-4-methoxy phenyl)-L-alanine methyl ester.

9. The antipode of claim 1 wherein said antipode isN,0-dicetyl-4-methoxy-L-m-tyrosine.

10. The antipode of claim 7 wherein said antipode isN-acetyl-3-(3-formyloxy-4-methoxy phenyl)-L- alanine.

11. The antipode of claim 7 wherein said antipode isN,0diacetyl-4-methoxy-L-m-tyrosine ethyl ester.

12. The antipode of claim 7 wherein said antipode isO-acetyl-N-formyl-4-methoxy-L-m-tyrosine.

13. An L-antipode of the formula:

wherein R is forrnylamino or loweralkanoylamino; R if formyl or loweralkanoyl; and R is carboxy or lower alkanoyloxy.

15 I 16 '14. The antipode of claim 13 wherein said antipode 16. Theantipode of claim 13 wherein said antipode isN-acetyl-3-(3-formyl-4-methoxy phenyU-L-alanine is N-acetyl-3-(3-acetyl-4-methoxy phenyU-L-alahine. methyl ester. 7 17. The antipode ofclaim 13 wherein said antipode 15. The antipode of claim 13 wherein saidantipode is 3-(3-acetyl-4-methoxy phenyl)-N-formyl-L-alanine. isN-acetyl-3-(3-formyl-4-meth0xy phenyl)-L-alanine ethyl ester.

1. THE L-ANTIPODE OF THE FORMULA:
 2. The antipode of claim 1 wherein Ris hydrogen.
 3. The antipode of claim 2 wherein said antipode is4-methoxy-L-m-tyrosine hydrochloride.
 4. The antipode of claim 2 whereinsaid antipode is 4-methoxy-L-m-tyrosine.
 5. The antipode of claim 1wherein R is lower alkyl.
 6. The antipode of claim 5 wherein saidantipode is 4-methoxy-L-m-tyrosine methyl ester.
 7. The L-antipode ofthe formula:
 8. The antipode of claim 7 wherein said antipode isN-acetyl 3-(3-formyloxy-4-methoxy phenyl)-L-alanine methyl ester.
 9. Theantipode of claim 1 wherein said antipode isN,0-dicetyl-4-methoxy-L-m-tyrosine.
 10. The antipode of claim 7 whereinsaid antipode is N-acetyl-3-(3-formyloxy-4-methoxy phenyl)-L-alanine.11. The antipode of claim 7 wherein said antipode isN,0-diacetyl-4-methoxy-L-m-tyrosine ethyl ester.
 12. The antipode ofclaim 7 wherein said antipode is0-acetyl-N-formyl-4-methoxy-L-m-tyrosine.
 13. An L-antipode of theformula:
 14. The antipode of claim 13 wherein said antipode isN-acetyl-3-(3-formyl-4-methoxy phenyl)-L-alanine methyl ester.
 15. Theantipode of claim 13 wherein said antipode isN-acetyl-3-(3-formyl-4-methoxy phenyl)-L-alanine ethyl ester.
 16. Theantipode of claim 13 wherein said antipode isN-acetyl-3-(3-acetyl-4-methoxy phenyl)-L-alanine.
 17. The antipode ofclaim 13 wherein said antipode is 3-(3-acetyl-4-methoxyphenyl)-N-formyl-L-alanine.